DERIVATIVES OF DEMETHYLPENCLOMEDINE:ANTICANCER AGENTS

本研究的目的是合成去甲苯氯美定的酰基、氨甲酰基和碳酸酯衍生物(DM-PEN)，这是一种抗肿瘤活性的、无神经毒性的潘氯美定(PEN)代谢物，临床评价药物因临床神经毒性而终止开发。这三个系列的新药将分别在人乳腺肿瘤异种移植瘤(MX-1)和人中枢神经系统肿瘤异种移植瘤(U251)皮下(Sc)或大脑内(Ic)进行评估，为在这一快速通道应用的第二阶段建议的进一步开发选择临床候选药物提供数据。PEN、DM-PEN及DM-PEN的乙酰衍生物均对MX-1移植瘤有抑制作用，而PEN及DM-PEN对一系列人脑肿瘤(脑胶质瘤、室管膜瘤)皮下移植瘤均有抑制作用。本项目的主要目的是评估DM-PEN的衍生物在脑肿瘤临床治疗中的应用，因为前者及其乙酰衍生物已被证明对IC移植的MX-1肿瘤具有活性，而DM-PEN和DM-PEN对一系列移植的人脑胶质瘤和室管膜瘤具有活性。建议的商业应用：这项研究的潜在商业应用是合成一种新型的DM-PEN衍生物，该衍生物可能对脑瘤或其他类型的癌症的治疗有临床好处。

The objective of the proposed research is to synthesize acyl, carbamyl and carbonate derivatives of demethypenclomedine (DM-PEN), the antitumor active, non-neurotoxic metabolite of penclomedine (PEN), a clinically- evaluated drug whose development was terminated because of clinical neurotoxicity. The three series of novel agents will be evaluated in a human breast tumor xenograft (MX-1) and in a human CNS tumor xenograft (U251) implanted subcutaneously (sc) or intracerebrally (ic), respectively, to provide data for selection of a clinical candidate for proposed further development in Phase II of this fast track application. PEN, DM-PEN and the acetyl derivative of DM-PEN were all active against ic-implanted MX-1 tumor, and PEN and DM-PEN were active against a series of human brain tumor xenografts (gliomas, ependymonas) implanted sc. The primary goal of this project is to evaluate derivatives of DM-PEN in the clinical treatment of brain tumors since the former and its acetyl derivative have been shown to be active against ic-implanted MX-1 tumor, and PEN and DM-PEN were active against a series of human gliomas and ependymomas implanted sc. PROPOSED COMMERCIAL APPLICATIONS: The potential commercial application of this research is the synthesis of a novel derivative of DM-PEN that may be of clinical benefit for the treatment of brain tumors or other types of cancer.